HCV-related advanced fibrosis/cirrhosis: randomized controlled trial of pegylated interferon alpha-2a and ribavirin

In patients with hepatitis C virus (HCV)-related advanced fibrosis/cirrhosis, 30% of sustained HCV clearance has been reported with pegylated interferon alpha-2a (PEG-IFN) alone, but the efficacy and tolerability of the PEG-IFN/ribavirin (RBV) combination remain poorly defined. A total of 124 treatment-naïve patients with biopsy proved HCV-related advanced fibrosis/cirrhosis (Ishak score F4-F6, Child-Pugh score < or =7) were randomized to 48 weeks of PEG-IFN (180 microg sc weekly) and standard dose of RBV (1000/1200 mg po daily, STD) or PEG-IFN (180 microg sc weekly) and low-dose of RBV (600/800 mg po daily, LOW). Sustained virologic response (SVR) rates with PEG-IFN/STD RBV (52%) were higher--albeit not significantly--than that with PEG-IFN/LOW RBV (38%, P = 0.153). In multivariate analysis, genotype 2/3 and a baseline platelet count > or =150 x 10(9)/L were independently associated with SVR. The likelihood of SVR was < 7% if viraemia had not declined by > or =2 log or to undetectable levels after 12 weeks. Nine adverse events in the STD RBV and 15 in the LOW RBV group were classified as severe (including two deaths); dose reductions for intolerance were required in 78% and 57% (P = 0.013), and treatment was terminated early in 23% and 27% of patients (P = n.s.). The benefit/risk ratio of treating compensated HCV-cirrhotics with STD PEG-IFN/RBV is favourable.

Treating open carious lesions in anxious children with ozone. A prospective controlled clinical study

PURPOSE: To determine whether the treatment of dental caries with ozone was possible in apprehensive children and to ascertain whether ozone reverses caries in open single-surface lesions. Further, the influence of ozone on laser fluorescence was investigated. METHODS: 82 lesions in 28 children with at least two open single-surface lesions were assessed. The children were anxious and were judged by the referring dentist as non-treatable. For each test lesion, which was treated with ozone, a control lesion was left without ozone treatment. Hardness and laser fluorescence values were assessed and the changes for hardness and laser fluorescence values in the test lesion were compared with the values in the control lesion after 2, 4, 6, and 8 months. RESULTS: 94 percent of the children were treatable and 93% lost their dental anxiety. The hardness values improved significantly in the ozone-treated test lesions after 4, 6, and 8 months (P< 0.05) compared with baseline while the control lesions had no significant change in hardness at any recall interval. Comparing the differences between test and control teeth over time, the laser fluorescence values improved, however the improvement was not statistically significant (P> 0.05). The use of ozone resulted in an average reduction of 13% of the laser fluorescence values immediately after the ozone treatment.

Alendronate with and without cholecalciferol for osteoporosis: results of a 15-week randomized controlled trial

OBJECTIVE: Many osteoporosis patients have low 25-hydroxyvitamin D (25OHD) and do not take recommended vitamin D amounts. A single tablet containing both cholecalciferol (vitamin D3) and alendronate would improve vitamin D status concurrently, with a drug shown to reduce fracture risk. This study assessed the efficacy, safety, and tolerability of a once-weekly tablet containing alendronate 70 mg and cholecalciferol 70 microg (2800 IU) (ALN + D) versus alendronate 70 mg alone (ALN). METHODS: This 15-week, randomized, double-blind, multi-center, active-controlled study was conducted during a season when 25OHD levels are declining, and patients were required to avoid sunlight and vitamin D supplements for the duration of the study. Men (n = 35) and postmenopausal women (n = 682) with osteoporosis and 25OHD >or= 9 ng/mL were randomized to ALN + D (n = 360) or ALN (n = 357). MAIN OUTCOME MEASURES: Serum 25OHD, parathyroid hormone, bone-specific alkaline phosphatase (BSAP), and urinary N-telopeptide collagen cross-links (NTX). RESULTS: Serum 25OHD declined from 22.2 to 18.6 ng/mL with ALN (adjusted mean change = -3.4; 95% confidence interval [CI]: -4.0 to -2.8), and increased from 22.1 to 23.1 ng/mL with ALN + D (adjusted mean change = 1.2; 95% CI: 0.6 to 1.8). At 15 weeks, adjusted mean 25OHD was 26% higher (p < 0.001, ALN + D versus ALN), the adjusted relative risk (RR) of 25OHD < 15 ng/mL (primary endpoint) was reduced by 64% (incidence 11% vs. 32%; RR = 0.36; 95% CI: 0.27 to 0.48 [p < 0.001]), and the RR of 25OHD < 9 ng/mL (a secondary endpoint) was reduced by 91% (1% vs. 13%; RR = 0.09; 95% CI: 0.03 to 0.23 [p < 0.001]). Antiresorptive efficacy was unaltered, as measured by reduction in bone turnover (BSAP and NTX). CONCLUSION: In osteoporosis patients who avoided sunlight and vitamin D supplements, this once-weekly tablet containing alendronate and cholecalciferol provided equivalent antiresorptive efficacy, reduced the risk of low serum 25OHD, improved vitamin D status over 15 weeks, and was not associated with hypercalcemia, hypercalciuria or other adverse findings, versus alendronate alone.

Efficacy and safety of intraarticular hylan or hyaluronic acids for osteoarthritis of the knee: a randomized controlled trial

OBJECTIVE: To compare the efficacy and safety of intraarticular hylan and 2 hyaluronic acids (HAs) in osteoarthritis (OA) of the knee. METHODS: This was a multicenter, patient-blind, randomized controlled trial in 660 patients with symptomatic knee OA. Patients were randomly assigned to receive 1 cycle of 3 intraarticular injections per knee of 1 of 3 preparations: a high molecular weight cross-linked hylan, a non-cross-linked medium molecular weight HA of avian origin, or a non-cross-linked low molecular weight HA of bacterial origin. The primary outcome measure was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at 6 months. Secondary outcome measures included local adverse events (effusions or flares) in injected knees. During months 7-12, patients were offered a second cycle of viscosupplementation. RESULTS: Pain relief was similar in all 3 groups. The difference in changes between baseline and 6 months between hylan and the combined HAs was 0.1 on the WOMAC pain score (95% confidence interval [95% CI] -0.2, 0.3). No relevant differences were observed in any of the secondary efficacy outcomes, and stratified analyses provided no evidence for differences in effects across different patient groups. There was a trend toward more local adverse events in the hylan group than in the HA groups during the first cycle (difference 2.2% [95% CI -2.4, 6.7]), and this trend became more pronounced during the second cycle (difference 6.4% [95% CI 0.6, 12.2]). CONCLUSION: We found no evidence for a difference in efficacy between hylan and HAs. In view of its higher costs and potential for more local adverse events, we see no rationale for the continued use of hylan in patients with knee OA.

Effects of percutaneous coronary interventions in silent ischemia after myocardial infarction: the SWISSI II randomized controlled trial

CONTEXT: The effect of a percutaneous coronary intervention (PCI) on the long-term prognosis of patients with silent ischemia after a myocardial infarction (MI) is not known. OBJECTIVE: To determine whether PCI compared with drug therapy improves long-term outcome of asymptomatic patients with silent ischemia after an MI. DESIGN, SETTING, AND PARTICIPANTS: Randomized, unblinded, controlled trial (Swiss Interventional Study on Silent Ischemia Type II [SWISSI II]) conducted from May 2, 1991, to February 25, 1997, at 3 public hospitals in Switzerland of 201 patients with a recent MI, silent myocardial ischemia verified by stress imaging, and 1- or 2-vessel coronary artery disease. Follow-up ended on May 23, 2006. INTERVENTIONS: Percutaneous coronary intervention aimed at full revascularization (n = 96) or intensive anti-ischemic drug therapy (n = 105). All patients received 100 mg/d of aspirin and a statin. MAIN OUTCOME MEASURES: Survival free of major adverse cardiac events defined as cardiac death, nonfatal MI, and/or symptom-driven revascularization. Secondary measures included exercise-induced ischemia and resting left ventricular ejection fraction during follow-up. RESULTS: During a mean (SD) follow-up of 10.2 (2.6) years, 27 major adverse cardiac events occurred in the PCI group and 67 events occurred in the anti-ischemic drug therapy group (adjusted hazard ratio, 0.33; 95% confidence interval, 0.20-0.55; P<.001), which corresponds to an absolute event reduction of 6.3% per year (95% confidence interval, 3.7%-8.9%; P<.001). Patients in the PCI group had lower rates of ischemia (11.6% vs 28.9% in patients in the drug therapy group at final follow-up; P = .03) despite fewer drugs. Left ventricular ejection fraction remained preserved in PCI patients (mean [SD] of 53.9% [9.9%] at baseline to 55.6% [8.1%] at final follow-up) and decreased significantly (P<.001) in drug therapy patients (mean [SD] of 59.7% [11.8%] at baseline to 48.8% [7.9%] at final follow-up). CONCLUSION: Among patients with recent MI, silent myocardial ischemia verified by stress imaging, and 1- or 2-vessel coronary artery disease, PCI compared with anti-ischemic drug therapy reduced the long-term risk of major cardiac events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00387231.

Full publication of results initially presented in abstracts

BACKGROUND: Abstracts of presentations at scientific meetings are usually available only in conference proceedings. If subsequent full publication of abstract results is based on the magnitude or direction of study results, publication bias may result. Publication bias, in turn, creates problems for those conducting systematic reviews or relying on the published literature for evidence. OBJECTIVES: To determine the rate at which abstract results are subsequently published in full, and the time between meeting presentation and full publication. To assess the association between study characteristics and full publication. SEARCH STRATEGY: We searched MEDLINE, EMBASE, The Cochrane Library, Science Citation Index, reference lists, and author files. Date of most recent search: June 2003. SELECTION CRITERIA: We included all reports that examined the subsequent full publication rate of biomedical results initially presented as abstracts or in summary form. Follow-up of abstracts had to be at least two years. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data. We calculated the weighted mean full publication rate and time to full publication. Dichotomous variables were analyzed using relative risk and random effects models. We assessed time to publication using Kaplan-Meier survival analyses. MAIN RESULTS: Combining data from 79 reports (29,729 abstracts) resulted in a weighted mean full publication rate of 44.5% (95% confidence interval (CI) 43.9 to 45.1). Survival analyses resulted in an estimated publication rate at 9 years of 52.6% for all studies, 63.1% for randomized or controlled clinical trials, and 49.3% for other types of study designs.'Positive' results defined as any 'significant' result showed an association with full publication (RR = 1.30; CI 1.14 to 1.47), as did 'positive' results defined as a result favoring the experimental treatment (RR =1.17; CI 1.02 to 1.35), and 'positive' results emanating from randomized or controlled clinical trials (RR = 1.18, CI 1.07 to 1.30).Other factors associated with full publication include oral presentation (RR = 1.28; CI 1.09 to 1.49); acceptance for meeting presentation (RR = 1.78; CI 1.50 to 2.12); randomized trial study design (RR = 1.24; CI 1.14 to 1.36); and basic research (RR = 0.79; CI 0.70 to 0.89). Higher quality of abstracts describing randomized or controlled clinical trials was also associated with full publication (RR = 1.30, CI 1.00 to 1.71). AUTHORS' CONCLUSIONS: Only 63% of results from abstracts describing randomized or controlled clinical trials are published in full. 'Positive' results were more frequently published than not 'positive' results.

A randomized controlled 1-year study of daily deferiprone plus twice weekly desferrioxamine compared with daily deferiprone monotherapy in patients with thalassemia major

BACKGROUND AND OBJECTIVES: The aim of this prospective, randomized, 1-year study was to compare the efficacy and safety of oral deferiprone (DFP) with those of combinations of parenteral desferrioxamine (DFO) with oral DFP. DESIGN AND METHODS: A total of 24 patients with thalassemia major were randomized to receive one of the following two treatments; DFP given at a daily dose of 75 mg/kg in combination with DFO (40-50 mg/kg twice weekly) (n=12) or as single agent (n=12). In addition, 12 patients treated with 40-50 mg/kg DFO 5 days weekly were included as a reference group without randomization. Changes in liver iron concentration (LIC) and serum ferritin (SF) were assessed; total iron excretion (TIE), urinary iron excretion (UIE) and iron balance were calculated. Cardiac function and toxicity were also examined. DESIGN AND METHODS: SF and LIC were significantly reduced after 1 year of combination therapy (p=0.01 and 0.07, respectively). A decrease of LIC was observed in all but one patient (87.5%) following the combination therapy but in only 42% of patients treated with DFP monotherapy. In the DFO reference group, a statistically significant decrease in LIC (p=0.01) associated with a substantial decrease in SF (p=0.08) was observed after 1 year. The combination regimen resulted in greater TIE compared to DFP monotherapy (p=0.08) and was the regimen associated with the highest iron balance compared to DFP monotherapy (p=0.04) or standard DFO treatment (p=0.006). INTERPRETATIONS AND CONCLUSIONS: The addition of subcutaneous DFO twice weekly to oral DFP 75 mg/kg is a highly efficacious and safe chelation therapy providing superior chelation activity to that of DFP and likely has an efficacy profile comparable to that of standard DFO.

Effects of rivastigmine on actigraphically monitored motor activity in severe agitation related to Alzheimer's disease: a placebo-controlled pilot study

Acetylcholinesterase inhibitors (AChEIs) are effective in the treatment of cognitive symptoms in Alzheimer's disease (AD). Because the behavioral and psychological symptoms of dementia (BPSD) have also been attributed to central cholinergic deficits, we examined whether the AChEI rivastigmine can reduce motor activity as measured in a rater-independent manner by wrist actigraphy in agitated AD patients. A total of 20 consecutive AD inpatients (13 females, 7 males, 80.4+/-9.1 years, S.D.) were included from our geriatric psychiatry unit, all of whom were exhibiting agitated behavior not attributable to delirium. Patients were assigned randomly and in a single-blinded fashion to rivastigmine 3mg or placebo for 14 days. Motor activity levels were monitored using an actigraph worn continuously on the wrist of the non-dominant hand. At the beginning and end of the study, patients were assessed using the Neuropsychiatric Inventory (NPI) and Nurses' Observation Scale for Geriatric Patients (NOSGER). Patients in the rivastigmine group exhibited less agitation than placebo recipients on the NPI-agitation subscale, but not on NOSGER. Actigraphic measurements showed a tendency towards reduced motor activity in the rivastigmine group. Because rivastigmine usually exerts its main effects after a longer period of time, the short-term effects seen in our study justify further controlled clinical trials examining the use of rivastigmine in BPSD by means of actigraphy.

Effects of anti-ischaemic drug therapy in silent myocardial ischaemia type I: the Swiss Interventional Study on Silent Ischaemia type I (SWISSI I): a randomized, controlled pilot study

AIMS: To determine the effect of anti-ischaemic drug therapy on long-term outcomes of asymptomatic patients without coronary artery disease (CAD) history but silent exercise ST-depression. METHODS AND RESULTS: In a randomized multicentre trial, 263 of 522 asymptomatic subjects without CAD but at least one CAD risk factor in whom silent ischaemia by exercise ECG was confirmed by stress imaging were asked to participate. The 54 (21%) consenting patients were randomized to anti-anginal drug therapy in addition to risk factor control (MED, n = 26) or risk factor control-only (RFC, n = 28). They were followed yearly for 11.2 +/- 2.2 years. During 483 patient-years, cardiac death, non-fatal myocardial infarction, or acute coronary syndrome requiring hospitalization or revascularization occurred in 3 (12%) of MED vs. 17 (61%) of RFC patients (P < 0.001). In addition, MED patients had consistently lower rates of exercise-induced ischaemia during follow-up, and left ventricular ejection fraction remained unchanged (-0.7%, P = 0.597) in contrast to RFC patients in whom it decreased over time (-6.0%, P = 0.006). CONCLUSION: Anti-ischaemic drug therapy and aspirin seem to reduce cardiac events in subjects with asymptomatic ischaemia type I. In such patients, exercise-induced ST-segment depression should be verified by stress imaging; if silent ischaemia is documented, anti-ischaemic drug therapy and aspirin should be considered.

Treating sensitive cervical areas with ozone. A prospective controlled clinical trial

PURPOSE: To determine whether the treatment of hypersensitive teeth with gaseous ozone (Healozone, KaVo 1600 ppm) for 60 seconds reduces pain immediately after treatment and in the longer term. METHODS: In three private practices in Switzerland, 31 subjects suffering from hypersensitive teeth were treated with gaseous ozone over a period of 54 weeks (one test and one control tooth in each subject). A cross-over design was chosen. The pain level was measured with a Visual Analogue Scale before and after the treatment. RESULTS: The subjects' pain level was reduced by 55% +/- 5.5% immediately after the ozone treatment. Over time, the pain level decreased significantly in all groups: The pain level in the test teeth was significantly reduced in Weeks 0-22 (treatment group, P < 0.001) compared to the pain level before treatment. The pain level in the control group was also reduced significantly over time in Weeks 0-22 (no-treatment, P = 0.025) and in Weeks 22-54 (treatment group, P = 0.0065). Comparing test and control teeth over time, there was no statistically significant difference in pain reduction (P = 0.58).

Clinical trials in head injury

Secondary brain damage, following severe head injury is considered to be a major cause for bad outcome. Impressive reductions of the extent of brain damage in experimental studies have raised high expectations for cerebral neuroprotective treatment, in the clinic. Therefore multiple compounds were and are being evaluated in trials. In this review we discuss the pathomechanisms of traumatic brain damage, based upon their clinical importance. The role of hypothermia, mannitol, barbiturates, steroids, free radical scavengers, arachidonic acid inhibitors, calcium channel blockers, N-methyl-D-aspartate (NMDA) antagonists, and potassium channel blockers, will be discussed. The importance of a uniform strategic approach for evaluation of potentially interesting new compounds in clinical trials, to ameliorate outcome in patients with severe head injury, is proposed. To achieve this goal, two nonprofit organizations were founded: the European Brain Injury Consortium (EBIC) and the American Brain Injury Consortium (ABIC). Their aim lies in conducting better clinical trials, which incorporate lessons learned from previous trials, such that the succession of negative, or incomplete studies, as performed in previous years, will cease.

Pain relief in ventilated preterms during endotracheal suctioning: a randomized controlled trial

BACKGROUND: In Switzerland approximately 8% of infants are born prematurely. Some of them undergo mechanical ventilation including endotracheal suctioning (ETS). ETS is one of the most frequently performed interventions and is linked to stress and pain, but its treatment is controversial. In Switzerland there is a lack of standardisation in pain relief for ETS. AIMS: To test the hypothesis that an intermittent dose of morphine reduces pain during ETS and that subsequent multisensorial stimulation (MSS), as a non pharmacological comforting intervention, helps infants to recover from experienced pain. METHOD: A randomized placebo controlled trial in two tertiary neonatal intensive care units (NICU) with a sample of 30 mechanically ventilated preterm infants was conducted. Pain was measured by three pain assessment tools (Bernese Pain Scale for Neonates, Premature Infant Pain Profile and Visual Analogue Scale) RESULTS: Morphine did not lead to any pain relief from ETS as measured by three pain scales. Nor did the comforting intervention of MSS show any effect. Repeated-measure analysis of variance for the within and between groups comparison showed no statistical significance. CONCLUSIONS: The administration of morphine for pain relief in ventilated preterm neonates during ETS remains questionable and the use of MSS as a comforting intervention after painful stimulus cannot be recommended. The validity testing of the instruments for this patient population should undergo a systematic validation trajectory. Future research should focus on options among non pharmacological interventions for relieving pain during ETS.